The candidate, Dr. Pati Irish, proposes a light and electron microscopic (LM;EM) analysis of the rat trigeminal which examines the lesion-induced, neuropathic changes in the immunoreactivity of five molecular markers present in the trigeminal subnucleus caudalis. The molecular markers include: glutamate, glutamate receptor (NMDAR2a/b), gamma aminobutyric acid, glycine, and tyrosine hydroxylase. Within the trigeminal nucleus, the analysis concentrates on lamina II of the subnucleus caudalis, which is the site of termination of the trigeminal afferent pain fibers. The data on changes in immunoreactivity will be interpreted in three- dimensional space, using methods of quantitative morphology. As part of the institute's role to the candidate, the University of Washington will provide courses and training in Quantitative Morphology, Neurophysiology, Neuroanatomy, Neuroplasticity, as well as clinical and academic seminars in Neurosurgery, and Pain Management. Also, the Department of Neurological Surgery plans to continue to involve Dr. Irish in a role as investigator in the ongoing CNS Center Grant and in its renewal (Oct. 95). The training complements the candidate's goals to use aspects of her previous training (LM,EM, and immunocytochemistry) to describe lesion- induced neuronal changes on a three-dimensional level which can be immediately relevant and useful to other investigators using computerized exchange of standardized information. The candidate's past goal was EM examination of the extracellular matrix of peripheral nerves well as the extracellular matrix immediately surrounding cultured cells. The present goal is EM analysis of trigeminal cells and their synapses with immediately surrounding neurons following nerve trauma. The candidates future goal is to function as an independent investigator examining and correlating the ultrastructural changes in neuronal structures and molecular markers with clinical changes in pain states. Pain mechanisms are extraordinarily complex, and presently remain obscure. Since no human model is possible which allows morphological analysis of lesion-induced changes in synaptic structure and molecules, this proposal represents a vital and necessary step in our understanding of the basic structural mechanisms of pain. Using quantitative morphology, this project has the power to move through the hierarchy of pain, from the level of the molecule to that of the organism.